The focus of genetic studies of addiction, as well as other common disorders, has been common genetic variants with MAF greater than 1%, and usually greater than 5%. The idea behind these studies is the common disease/common variant (CD/CV) hypothesis according to which common alleles of ancient origin and with small to moderate effect lead to susceptibility to common disorders. However, recent evidence suggests that rare variants of stronger effect might substantially contribute to the genetic vulnerability to common diseases (for review see Ref.118). For schizophrenia and autism, multiple risk rare variants with moderate to large effect sizes have been already reported.119,120 Some of these variants appear to be associated with severe forms of disease and are thought to be of recent origin or de novo in sporadic cases. The contribution of rare variants in addictions is largely unknown. However, recent advances in sequencing technologies have opened the way for extensive searches for rare variants. The ability to detect and connect rare variants to behavior can be maximized by the study of genetically related individuals in families and founder populations
